The present invention relates to organic chemistry, medicinal chemistry, biochemistry, pharmacology and medicine. In particular, it relates to uridyl peptide antibiotic (UPA) derivatives, their synthesis and their use in the treatment of bacterial infection.
The following is offered as background information only and In is not admitted to be, or to describe, prior art to the present invention.
Despite the emergence of new and potent antibiotics, e.g., beta-lactams, macrolides, quinolones, tetracyclines and aminoglycosides, the incidence of bacterial resistance to antibiotics continues to increase at an alarming rate. Furthermore, cross-resistance, the ability of a bacterium resistant to one antibiotic to resist other different antibiotic(s) is also on the rise. To combat these phenomena, there is a need not merely for new antibiotic compounds but for new classes of antibiotics which are sufficiently different in structure and mode of action from current antibiotics to decrease the rate at which resistance arises and to reduce the chances of cross-resistance.
The uridyl peptide antibiotics (UPAs) appear to be such a class of antibiotic compounds. In the first place, their chemical structures, shown below, are unique among current therapeutic antibiotics:
Furthermore, the UPAs share a bacterial cellular target which is likewise unique among current antibiotics. That target is bacterial translocase I (phospho-N-acetylmuramyl-pentapeptide translocase), an enzyme that catalyzes the first reaction in the membrane-bound cycle of reactions in bacterial peptidoglycan biosynthesis, e.g., in E. coli the transfer of phospho-MurNAc-L-Ala-xcex3-D-Glu-m-DAP-D-Ala-D-Ala from UMP to a membrane bound carrier, undecaprenyl phosphate. There are other translocase inhibitors, such as tunicamycin (Compound 1) and amphomycin (Compound 2), 
Asp=aspartic acid
Gly=glycine
Val=valine
Pro=proline
Dabe=D-erythro-xcex1,xcex2-diaminobutyric acid
Dabt=L-threo-xcex1,xcex2-diaminobutyric acid
Pip=D-pipecolic acid
however, in addition to inhibiting bacterial translocase, these compounds also inhibit mammalian enzymes that catalyze the formation of lipid-linked saccharides through which membrane and secreted proteins are glycosylated which precludes their use as therapeutic antibiotics. On the other hand, the mureidomycins (and, it would be expected, the structurally similar pacidamycins napsamycins), while inhibiting bacterial translocase I similarly to tunicamycin and amphomycin, do not inhibit either bacterial or mammalian lipid-linked saccharide formation (Inukai, M., Antimicrobial Agents and Chemotherapy, 1992, 980-83). The UPAS, then, would appear to be excellent targets for the development of novel therapeutic antibiotics.
Our own efforts to develop novel therapeutic antibiotics to treat and prevent bacterial infections has resulted in the synthesis of dihydro derivatives of uridyl peptide antibiotics which are active against a variety of bacteria including, significantly, several species which are displaying resistance to current antibiotic therapies.
Thus, in one aspect the present invention relates generally to dihydro derivatives, and their physiologically acceptable salts and prodrugs, of uridyl peptide antibiotics. In addition, the present invention relates to the preparation of pharmaceutical compositions of the dihydro derivatives, and their physiologically acceptable salts and prodrugs, and the use of the compositions for the prevention and treatment of bacterial infections.
As used herein, xe2x80x9curidyl peptide antibioticxe2x80x9d refers to a compound having the core structure: 
As used herein, xe2x80x9cdihydro uridyl peptide antibioticxe2x80x9d refers to a compound having the core structure: 
As used herein, xe2x80x9ctetrahydro uridyl peptide antibioticxe2x80x9d refers to a compound having the core structure: 
As used herein, xe2x80x9cpharmaceutical compositionxe2x80x9d refers to a mixture of one or more of the compounds described herein, or physiologically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically acceptable carriers and/or excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
As used herein, a xe2x80x9cphysiologically acceptable carrierxe2x80x9d refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
An xe2x80x9cexcipient,xe2x80x9d as used herein, refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
A xe2x80x9cprodrugxe2x80x9d refers to an agent which is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the xe2x80x9cprodrugxe2x80x9d) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial.
1. Chemistry
A. General structural features.
Thus, in one aspect, this invention relates to a compound having the chemical structure: 
Rx is selected from the group consisting of a first amino acid and a first polypeptide, the first amino acid or the first polypeptide being optionally substituted with one or more groups independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heteroalicyclic.
Ry is selected from the group consisting of a second amino acid and a second polypeptide, the second amino group or the second polypeptide being optionally substituted with one or more groups independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heteroalicyclic.
The second amino acid or a terminal amino acid of the second polypeptide is linked through its xcex1-amino nitrogen atom to an xcex1-amino nitrogen atom of a third amino acid or a third polypeptide by a carbonyl group, the third amino acid or the third polypeptide being optionally substituted with one or more groups independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heteroalicyclic.
R4 and R5 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heteroalicyclic.
R8 is uracil or dihydrouracil optionally substituted with a group selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteralicyclic, halo, cyano, nitro and xe2x80x94NRRxe2x80x2.
R9 and R10 are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, mercapto, alkylthio, halo, cyano, and xe2x80x94NRRxe2x80x2.
R and Rxe2x80x2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, carbonyl, C-carboxy and O-carboxy.
As used herein, the term xe2x80x9calkylxe2x80x9d refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as xe2x80x9c1 to 20xe2x80x9d refers to each integer in the given range; e.g., xe2x80x9c1 to 20 carbon atomsxe2x80x9d means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. 20 carbon atoms). More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more individually selected from cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, and xe2x80x94NRRxe2x80x2, R and Rxe2x80x2 being as defined above.
A xe2x80x9ccycloalkylxe2x80x9d group refers to an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group wherein one of more of the rings does not have a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, X cyclohexadiene, cycloheptane and, cycloheptatriene. A cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more individually selected from alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, carboxy, O-carbamyl, N-carbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro and xe2x80x94NRRxe2x80x2, with R and Rxe2x80x2 being as defined above.
An xe2x80x9calkenylxe2x80x9d group refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond.
An xe2x80x9calkynylxe2x80x9d group refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
An xe2x80x9carylxe2x80x9d group refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl (a monocyclic aryl), naphthalenyl (a bicyclic aryl) and anthracenyl (a tricyclic aryl). The aryl group may be substituted or unsubstituted. When substituted, the substituted group(s) is preferably one or more selected from halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, Q-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, S-sulfonamido, N-sulfonamido, trihalomethanesulfonamido and xe2x80x94NRRxe2x80x2, R and Rxe2x80x2 being as defined above.
As used herein, a xe2x80x9cheteroarylxe2x80x9d group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. Examples, without limitation, of heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine. The heteroaryl group may be substituted or unsubstituted. When substituted, the substituted group(s) is preferably one or more selected from alkyl, cycloalkyl, halo, trihalomethyl, hydroxy, alkoxy, aryl, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, sulfonamido, carboxy, sulfinyl, sulfonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido and xe2x80x94NRRxe2x80x2, R and Rxe2x80x2 being as defined above.
A xe2x80x9cheteroalicyclicxe2x80x9d group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. The heteroalicyclic ring may be substituted or unsubstituted. When substituted, the substituted group(s) is preferably one or more selected from alkyl, cycloalkyl, aryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, sulfinyl, sulfonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido and xe2x80x94NRRxe2x80x2, R and Rxe2x80x2 being as defined above.
A xe2x80x9cheteroaryl/aryl bicyclicxe2x80x9d group refers to a group of general structure 1 wherein the xe2x80x9cAxe2x80x9d ring is aryl and the B ring is heteroaryl. The xe2x80x9cAxe2x80x9d and xe2x80x9cBxe2x80x9d rings are independently five or six member rings. The heteroaryl/aryl bicyclic is covalently bonded in a compound of this invention through the B ring. 
A xe2x80x9cheteroalicylic/aryl bicyclicxe2x80x9d group refers to a group of general structure 1 wherein the xe2x80x9cAxe2x80x9d ring is aryl and the xe2x80x9cBxe2x80x9d ring is heteroalicyclic. The heteroalicylic/aryl bicyclic group is covalently bonded in a compound of this invention through the xe2x80x9cBxe2x80x9d ring.
A xe2x80x9cheteroaryl/heteroaryl bicyclicxe2x80x9d group refers to a group general structure wherein the xe2x80x9cAxe2x80x9d ring and the xe2x80x9cBxe2x80x9d rings are heteroaryl. The heteroaryl/heteroaryl bicyclic group is covalently bonded in a compound of this invention through xe2x80x9cBxe2x80x9d ring.
A xe2x80x9cheteroalicylic/heteroaryl bicyclicxe2x80x9d group refers to a group of general structure 1 wherein the xe2x80x9cAxe2x80x9d ring is heteroaryl and the xe2x80x9cBxe2x80x9d ring is heteroalicyclic. The heteroalicylic/heteroaryl bicyclic group is covalently bonded in a compound of this invention through the xe2x80x9cBxe2x80x9d ring.
A xe2x80x9chydroxyxe2x80x9d group refers to an xe2x80x94OH group.
An xe2x80x9calkoxyxe2x80x9d group refers to both an xe2x80x94O-alkyl and an xe2x80x94O-cycloalkyl group, as defined herein.
An xe2x80x9caryloxyxe2x80x9d group refers to both an xe2x80x94O-aryl and an xe2x80x94O-heteroaryl group, as defined herein.
A xe2x80x9cmercaptoxe2x80x9d group refers to an xe2x80x94SH group.
An xe2x80x9calkylthioxe2x80x9d group refers to both an S-alkyl and an xe2x80x94S-cycloalkyl group, as defined herein.
An xe2x80x9carylthioxe2x80x9d group refers to both an xe2x80x94S-aryl and an xe2x80x94S-heteroaryl group, as defined herein.
A xe2x80x9ccarbonylxe2x80x9d group refers to a xe2x80x94C(xe2x95x90O)xe2x80x94Rxe2x80x3 group, where Rxe2x80x3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), as these are defined herein.
An xe2x80x9caldehydexe2x80x9d group refers to a carbonyl group where Rxe2x80x3 is hydrogen.
A xe2x80x9cthiocarbonylxe2x80x9d group refers to a xe2x80x94C(xe2x95x90S)xe2x80x94Rxe2x80x3 group, with Rxe2x80x3 as defined herein,
An xe2x80x9cO-carboxyxe2x80x9d group refers to a Rxe2x80x3C(xe2x95x90O)O-group, with Rxe2x80x3 as defined herein.
A xe2x80x9cC-carboxyxe2x80x9d group refers to a xe2x80x94C(xe2x95x90O)ORxe2x80x3 group with Rxe2x80x3 as defined herein.
An xe2x80x9cacetylxe2x80x9d group refers to a xe2x80x94C(xe2x95x90O)CH3 group.
A xe2x80x9ccarboxyalkylxe2x80x9d group refers to xe2x80x94(CH2)rC(xe2x95x90O)ORxe2x80x3 wherein r is 1-6 and Rxe2x80x3 is as defined above.
A xe2x80x9ccarboxylic acidxe2x80x9d group refers to a C-carboxy group in which Rxe2x80x2, is hydrogen.
A xe2x80x9chaloxe2x80x9d group refers to fluorine, chlorine, bromine or iodine.
A xe2x80x9ctrihalomethylxe2x80x9d,group refers to a xe2x80x94CX3 group wherein X is a halo group as defined above.
A xe2x80x9ctrihalomethanesulfonylxe2x80x9d, group refers to a X3CS(xe2x95x90O)2-group with X as defined above.
A xe2x80x9ccyanoxe2x80x9d group refers to a xe2x80x94Cxe2x89xa1N group.
An xe2x80x9cisocyanatoxe2x80x9d group refers to a xe2x80x94NCO group.
A xe2x80x9cthiocyanatoxe2x80x9d group refers to a xe2x80x94CNS group.
An xe2x80x9cisothiocyanatoxe2x80x9d group refers to a xe2x80x94NCS group.
A xe2x80x9csulfinylxe2x80x9d group refers to a xe2x80x94S(xe2x95x90O)xe2x80x94Rxe2x80x3 group, with Rxe2x80x3 as defined herein.
A xe2x80x9csulfonylxe2x80x9d group refers to a xe2x80x94S(xe2x95x90O)2Rxe2x80x3 group, with Rxe2x80x3 as defined herein.
A xe2x80x9cS-sulfonamidoxe2x80x9d group refers to a xe2x80x94S(xe2x95x90O)2NRRxe2x80x2 group, with R and Rxe2x80x2 as defined herein.
A xe2x80x9cN-sulfonamidoxe2x80x9d group refers to a RS(xe2x95x90O)2NH-group with R as defined herein.
A xe2x80x9ctrihalomethanesulfonamidoxe2x80x9d group refers to a X3CS(xe2x95x90O)2NH-group with X as defined herein.
An xe2x80x9cO-carbamylxe2x80x9d group refers to a xe2x80x94OC(xe2x95x90O)NRRxe2x80x2 group with R and Rxe2x80x2 as defined herein.
An xe2x80x9cN-carbamylxe2x80x9d group refers to a ROC(xe2x95x90O)NH-group, with R as defined herein.
An xe2x80x9cO-thiocarbamylxe2x80x9d group refers to a xe2x80x94OC(xe2x95x90S)xe2x80x94NRRxe2x80x2 group with R and Rxe2x80x2 as defined herein.
An xe2x80x9cN-thiocarbamylxe2x80x9d, group refers to an ROC(xe2x95x90S)NH-group, with R as defined herein.
A xe2x80x9cC-amidoxe2x80x9d group refers to a xe2x80x94C(xe2x95x90O)xe2x80x94NRRxe2x80x2 group with R and Rxe2x80x2 as defined herein.
An xe2x80x9cN-amidoxe2x80x9d group refers to a RC(xe2x95x90O)NH-group, with R as defined herein.
A xe2x80x9cnitroxe2x80x9d group refers to a xe2x80x94NO2 group.
A xe2x80x9ctert-butylxe2x80x9d group refers to a (CH3)3Cxe2x80x94 group.
An xe2x80x9cisopropylxe2x80x9d group refers to a (CH3)2CHxe2x80x94 group.
A xe2x80x9cureidoxe2x80x9d group refers to a xe2x80x94NHC(xe2x95x90O)NRRxe2x80x2 with R and Rxe2x80x2 as defined herein.
A xe2x80x9camidinoxe2x80x9d group refers to a RRxe2x80x2NC(xe2x95x90NH)xe2x80x94 group with R and Rxe2x80x2 as defined herein.
A xe2x80x9cguanidinoxe2x80x9d group refers to a xe2x80x94NHC(xe2x95x90NH)NRRxe2x80x2 with R and Rxe2x80x2 as defined herein.
An xe2x80x9cammoniumxe2x80x9d group refers to an xe2x80x94NHRRxe2x80x2 group with R and Rxe2x80x2 as defined herein.
A xe2x80x9cpolypeptidylxe2x80x9d group refers to a group formed by the covalent bonding of the amino group of an xcex1-amino acid with the carboxy group of another amino acid. A great many amino acids may be bonded to one another in this manner; i.e., a polypeptidyl group has the general formula: 
wherein Ra, Rb, and Rc, may be the same or different depending on the amino acid used. Of course, as the number of Rb""s increases with xe2x80x9cnxe2x80x9d, each Rb may be the same or different. If xe2x80x9cnxe2x80x9d is 0, then the polypeptide would be referred to as a xe2x80x9cdipeptidylxe2x80x9d, group; if xe2x80x9cnxe2x80x9d is 1, the molecule would be referred to as a xe2x80x9ctripeptidyl,xe2x80x9d group; etc. As used herein, a xe2x80x9cpolypeptidylxe2x80x9d refers to a linear chain of amino acids wherein n is 3-18 (i.e., 5 to 20 amino acids linked head to tail); preferably a xe2x80x9cpolypeptidexe2x80x9d of this invention is dipeptidyl, a tripeptidyl or a tetrapeptidyl group; most preferably, a polypeptidyl group of this invention is a dipeptidyl group. The amino acid on the left hand side of the above formula is referred to as the N-terminal amino acid residue and the amino acid on the right hand side is referred to as the C-terminal amino acid residue.
By xe2x80x9camino acidxe2x80x9d is meant a compound selected from the group consisting of alanine, arginine, asparagine, cysteine, cystine, 3,5-dibromotyrosine, 3,5-diiodotyrosine, glutamic acid, glutamine, glycine, histidine, hydroxylysine, hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, thyroxine, tryptophane, tyrosine and valine.
By xe2x80x9ccombined,xe2x80x9d when referring to two adjacent xe2x80x9cRxe2x80x9d groups herein is meant that the two xe2x80x9cRxe2x80x9d groups are covalently bonded to y each other so as to form a ring system. As used herein, the ring system may be heteroaryl, heteroalicyclic, heteroaryl/aryl bicyclic, heteroalicyclic/aryl bicyclic, heteroaryl/heteroaryl bicyclic or a heteroaryl/heteroalicyclic bicyclic.
A xe2x80x9curacilxe2x80x9d group has the chemical structure: 
A xe2x80x9cdihydrouracilxe2x80x9d has the chemical structure: 
A xe2x80x9c6-hydroxytetrahydroisoquinolin-3-ylxe2x80x9d group has the chemical structure: 
A xe2x80x9c1-methyl-6-hydroxytetrahydroisoquinolin-3-ylxe2x80x9d, group has the chemical structure: 
A xe2x80x9cstereochemical configurationxe2x80x9d refers to the three dimensional relationship of the substituents on an asymmetric carbon atom (a carbon atom with four different group attached to it). If a specific stereochemistry is not shown at a particular asymmetric carbon atom of a compound of this invention, unless expressly stated otherwise in the text the configuration at that carbon may be either R or S.
A compound of this invention that is capable of inhibiting the growth of bacteria is yet another aspect of this invention.
By xe2x80x9cinhibiting the growthxe2x80x9d is meant slowing, preferably stopping the proliferation of a bacterium as the result of the presence of a compound or compounds of this invention under conditions which normally would favor such growth in the absence of the compound or compounds. Preferably, such inhibition of growth or proliferation includes the destruction of individual bacteria.
A compound of this invention that is capable of selectively inhibiting the growth of bacteria is a further aspect of this invention.
By xe2x80x9cselectivelyxe2x80x9d is meant that the compound inhibits bacterial cellular processes while having no or very little effect on the cellular processes of a patient species. One way to measure the selectivity would be to compare the MIC (defined below) of a compound of this invention for cellular processes in a patient species with the MIC for inhibition of bacterial growth for the subject bacteria. A ratio of patient species MIC to bacterial MIC of from 10 to 10,000 would indicate selectivity; preferably the ratio would be from 100 to 10,000; most preferably from 1,000 to 10,000.
A compound of this invention that inhibits bacterial translocase I is yet another aspect of this invention.
That the bacteria which are inhibited by a compound of this invention are of the genus Pseudomonas, Eschericia, Staphylococcus, Streptococcus, Enterococcus, Mycobacteria or Haemophilus is a still further aspect of this invention.
B. Preferred structural features.
A preferred aspect of this invention relates to a compound having the chemical structure: 
R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, carbonyl, sulfonyl, trihalomethanesulfonyl, C-carboxy, O-carboxy, C-amido, cyano, hydroxy, alkoxy, xe2x80x94NRRxe2x80x2, amino acid, polypeptidyl, combined with one another, a heteroaryl or a heteroalicyclic and, combined with R3 a heteroaryl, a heteroalicyclic, a heteroaryl/aryl bicyclic, a heteroalicyclic/aryl bicyclic, a heteroaryl/heteroaryl bicyclic or a heteroalicyclic/heteroaryl bicyclic.
R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, C-carboxy, C-amido and, combined with R2, a heteroaryl, a heteroalicyclic, a heteroaryl/aryl bicyclic, a heteroalicyclic/aryl bicyclic, a heteroaryl/heteroaryl bicyclic and a heteroalicyclic/heteroaryl bicyclic.
R4 and R5 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl.
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, C-carboxy and C-amido.
R8 is uracil or dihydrouracil optionally substituted with a group selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, cyano, nitro and xe2x80x94NRRxe2x80x2.
R9 and R10 are selected from the group consisting of hydrogen, halo, cyano, hydroxy, alkoxy, mercapto, alkylthio and xe2x80x94NRRxe2x80x2.
The variable xe2x80x9cnxe2x80x9d may be 0 or 1.
R and Rxe2x80x2 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, carbonyl, sulfonyl, and, combined, a five-member or a six-member heteroalicyclic ring.
A further presently preferred embodiment of this invention is that n is 1 and R1 and R2 are independently selected from the group consisting of hydrogen, amino acid, dipeptidyl, tripeptide, tetrapeptide and, combined with R3, a heteroalicyclic/aryl bicyclic or a heteroalicyclic/heteroaryl bicyclic.
It is also a presently preferred embodiment of this invention that R3 is selected from the group consisting of hydrogen, lower alkyl, monocyclic aryl and bicyclic aryl.
It is presently preferred that R4 and R5 are independently selected from the group consisting of hydrogen and lower alkyl.
Another presently preferred embodiment of this invention is that R6 and R7 are independently selected from the group consisting of hydrogen, lower alkyl, monocyclic aryl and bicyclic aryl.
A further presently preferred embodiment of this invention is that R8 is uracil or dihydrouracil optionally substituted with a group selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, halo, hydroxy, alkoxy, mercapto and alkylthio.
Likewise, a presently preferred embodiment of this invention is that R9 is selected from the group consisting of hydrogen, halo, hydroxy, alkoxy, mercapto and alkylthio.
Yet another presently preferred embodiment of this invention is that R10 is selected from the group consisting of hydrogen and hydroxy.
A further preferred embodiment of this invention at present also is that n is 1 and R1 and R2 are independently selected from the group consisting of hydrogen, amino acid, dipeptidyl, and combined with R3, a heteroalicyclic/aryl bicyclic.
Similarly, it is a further presently preferred embodiment of this invention that R3 is selected from the group consisting of
hydrogen;
lower alkyl optionally substituted with one or more groups selected from the group consisting of halo, cyano, nitro, hydroxy, lower alkoxy, mercapto, (lower alkyl)thio, xe2x80x94NRRxe2x80x2, guanidino, amidino, ureido, C-carboxy,
aryl optionally substituted with one or more group selected from the group consisting of
lower alkyl, trihalomethyl, lower alkoxy, (lower alkyl)thio, halo, hydroxy, mercapto, nitro, cyano and xe2x80x94NRRxe2x80x2,
heteroaryl optionally substituted with one or more groups selected from the group consisting of
lower alkyl, lower alkoxy, (lower alkyl)thio, halo, hydroxy, mecapto, nitro, cyano and xe2x80x94NRRxe2x80x2,
heteroaryl optionally substituted with one or more groups selected from the group consisting of lower alkyl, lower alkoxy, (lower alkyl)thio, halo, hydroxy, mercapto, nitro, cyano and xe2x80x94NRRxe2x80x2; and,
combined with R2 a six-member heteroalicyclic/aryl or heteroalicyclic/heteroaryl bicyclic.
A still further presently preferred embodiment of this invention is that R4 and R5 are independently selected from the group consisting of hydrogen and lower alkyl.
Another presently preferred embodiment of this invention is that R6 and R7 are independently selected from the group consisting of
hydrogen;
lower alkyl optionally substituted with a one or more groups selected from the group consisting of halo, cyano, nitro, hydroxy, lower alkoxy,. mercapto, (lower alkyl)thio, amidino, guanidino, amidino, ureido, xe2x80x94NRRxe2x80x2, C-carboxy,
aryl optionally substituted with one or more group selected from the group consisting of
lower alkyl, trihalomethyl, lower alkoxy, (lower alkyl)thio, halo, hydroxy, mercapto, nitro, cyano and xe2x80x94NRRxe2x80x2, and
heteroaryl optionally substituted with one or more groups selected from the group consisting of
lower alkyl, (trihalomethyl), lower alkoxy, (lower alkyl)thio, halo, hydroxy, mercapto, nitro, cyano and xe2x80x94NRRxe2x80x2, and,
heteroaryl optionally substituted with one or more groups selected from the group consisting of lower alkyl, lower alkoxy, (lower alkyl)thio, halo, hydroxy, mercapto, nitro, cyano and xe2x80x94NRRxe2x80x2.
Yet another presently preferred embodiment of this invention is that R8 is uracil or dihydrouracil optionally substituted with a group selected from the group consisting of hydrogen, lower alkyl, lower alkenyl and halo.
It is also a presently preferred embodiment of this invention that R9 is selected from the group consisting of hydrogen, halo and hydroxy.
A further presently preferred embodiment of this invention is that R10 is selected from the groups consisting of hydrogen and hydroxy.
A presently particularly preferred embodiment of this invention is that
n is 1;
R1 and R2 are both hydrogen or R1 is hydrogen and R2 is combined with R3 to give 6-hydroxyisoquinolin-3-yl or 1-methyl-6hydroxyisoquinoline-3-yl;
R3 is selected from the group consisting of
hydrogen;
lower alkyl, optionally substituted with a group selected from the group consisting of hydroxy, thichydroxy, lower alkyl alkoxy, lower alkyl alkylthio, halo, amino, xe2x80x94NRRxe2x80x2 and
aryl, optionally substituted with one or more groups selected from the group consisting of
lower alkyl, trihalomethyl, hydroxy, lower alkyl alkoxy, lower alkyl alkylthio, halo, nitro amino and xe2x80x94NRRxe2x80x2; and,
combined with R2, 6-hydroxyisoquinolin-3-yl or 1-methyl-6hydroxyisoquinolin-3-yl;
R4 and R5 are methyl;
R6 is selected from the group consisting of
lower alkyl optionally substituted with a group selected from the group consisting of hydroxy, lower alkoxy, (lower alkyl)thio, halo,xe2x80x94NRRxe2x80x2, cyclohexyl,
aryl, optionally substituted with one or more groups selected from the group consisting of
hydroxy, lower alkoxy, (lower alkyl)thio, halo, trihalomethyl, nitro, xe2x80x94NRRxe2x80x2, and phenyl, and,
heteroaryl, optionally substituted with one or more groups selected from the group consisting of
hydroxy, lower alkoxy, (lower alkyl)thio, halo, trihalomethyl, nitro, xe2x80x94NRRxe2x80x2, and phenyl;
R7 is selected from the group consisting of
lower alkyl substituted with a group selected from the group consisting of
aryl optionally substituted with one or more groups selected from the group consisting of
hydroxy, lower alkoxy, (lower alkyl)thio, halo, trihalomethyl, nitro, xe2x80x94NRRxe2x80x2 and phenyl,
heteroaryl optionally substituted with one or more groups selected from the group consisting of
hydroxy, lower alkoxy, (lower alkyl)thio, halo, trihalomethyl, nitro, xe2x80x94NRRxe2x80x2 and phenyl, and
aryl, optionally substituted with one or more groups selected from the group consisting of hydroxy, lower alkoxy, (lower alkyl)thio, halo, trihalomethyl, nitro, xe2x80x94NRRxe2x80x2 and phenyl;
R8 is uracil or dihydrouracil;
R9 is hydroxy;
R10 is hydrogen; and,
R and Rxe2x80x2 are independently selected from the group consisting of hydrogen and lower alkyl.
It is another presently particularly preferred embodiment of this invention that an xe2x80x9carylxe2x80x9d group in any of the above embodiments is phenyl or naphthyl.
It is also a presently particularly preferred embodiment of this invention that a xe2x80x9cheteroarylxe2x80x9d group in any of the above embodiments is selected from the group consisting of indol-3-yl, thien-2-yl, benzothien-3-yl, thiazol-4-yl, imidazol-2-yl and imidazol-4-yl.
It is also a presently preferred embodiment of this invention that n is 0 and R1 is selected from the group consisting of lower alkyl substituted with one or more groups selected from the group consisting of xe2x80x94NRRxe2x80x2, N-piperazinyl and an aryl group which is itself substituted with one or more groups selected from the group consisting of xe2x80x94NRRxe2x80x2 and lower alkyl substituted with one or more xe2x80x94NRRxe2x80x2 groups.
Table 2 shows additional presently preferred embodiment of this invention.
A further presently preferred embodiment of this invention is a method for the synthesis of a compound of this invention comprising reacting hydrogen gas in the presence of a catalytic reducing agent in a solvent at ambient temperature with a compound having the chemical structure: 
wherein,
R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, carbonyl, C-carboxy, O-carboxy, C-amido, cyano, hydroxy, alkoxy, xe2x80x94NRRxe2x80x2, amino acid, polypeptidyl, combined with one another, a heteroaryl or a heteroalicyclic and, combined with R2 a heteroaryl, a heteroalicyclic, a heteroaryl/aryl bicyclic, a heteroalicyclic/aryl bicyclic, a heteroaryl/heteroaryl bicyclic or a heteroalicyclic/heteroaryl bicyclic; R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, C-carboxy, C-amido and, combined with R2, a heteroaryl, a heteroalicyclic, a heteroaryl/aryl bicyclic, a heteroalicyclic/aryl bicyclic, a heteroaryl/heteroaryl bicyclic and a heteroalicyclic/heteroaryl bicyclic;
R4 and R5 are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, C-carboxy and C-amido;
R8 is uracil or dihydrouracil optionally substituted with a group selected from the group consisting of alkyl, aryl, heteroaryl, heteroalicyclic, halo, cyano, nitro and xe2x80x94NRRxe2x80x2;
R9 and R10 are independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, alkoxy and xe2x80x94NRRxe2x80x2;
n is 0 or 1; and,
R and Rxe2x80x2 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and, combined, a five-member or a six-member heteroalicyclic ring.
As used herein, a xe2x80x9csolventxe2x80x9d refers to a protic or an aprotic solvent; preferably it is an aprotic solvent. A xe2x80x9cprotic solventxe2x80x9d is a solvent which has hydrogen atom(s) covalently bonded to oxygen or nitrogen atoms which renders the hydrogen atoms appreciably acidic and thus capable of being xe2x80x9csharedxe2x80x9d with a solute through hydrogen bonding. Examples of protic solvents include, without limitation, water and alcohols.
An xe2x80x9caprotic solventxe2x80x9d may be polar or non-polar but, in either case, does not contain acidic hydrogens and therefore is not capable of hydrogen bonding with solutes. Examples, without limitation, of non-polar aprotic solvents, are pentane, hexane, benzene, toluene, methylene chloride, chlorform and carbon tetrachloride. Examples of polar aprotic solvents are tetrahydrofuran, dimethylsulfoxide and dimethylformamide.
In a presently preferred embodiment of this invention, the solvent is a polar aprotic solvent, preferably dimethylformamide.
The reaction may be carried out at atmospheric pressure or at increased pressures. By xe2x80x9cincreased pressurexe2x80x9d is meant any pressure above atmospheric pressure. In a presently preferred embodiment of this invention, the reaction is performed at atmospheric pressure.
By xe2x80x9cambient temperaturexe2x80x9d is meant the temperature of the reaction solution in the absence of any external heating.
xe2x80x9cCatalytic reducing agentsxe2x80x9d as used herein refers to agents which catalyze the addition of hydrogen to unsaturated (i.e., containing double or triple bonds) compounds and are well known to those skilled in the art. Examples, without limitation, of such reagents are Palladium on carbon (Pd/C), platinum on carbon (Pt/C) and Raney Nickel (Raxe2x80x94Ni). The presently preferred catalytic reducing agent is 10% Pd/C.
3. Biochemistry/Pharmacotherapy
A pharmaceutical composition comprising a compound of this invention and a pharmaceutically acceptable carrier and/or excipient is yet another presently preferred embodiment of this invention.
A method for inhibiting the growth of bacteria comprising contacting said bacteria with a compound, salt or prodrug of a compound of this invention, is a further presently preferred embodiment of this invention.
The term xe2x80x9cmethodxe2x80x9d refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by, practitioners of the chemical, pharmaceutical, biological, biochemical and medical arts.
The term xe2x80x9ccontactingxe2x80x9d as used herein refers to bringing a compound of this invention and a target bacteria strain together in such a manner that the compound can affect the growth of the bacteria. Such xe2x80x9ccontactingxe2x80x9d can be accomplished xe2x80x9cin vitro,xe2x80x9d i.e., in a test tube, a petri dish or the like. In a test tube, contacting may involve only a compound and a bacterial strain of interest or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment. In this context, the ability of a particular compound to affect a disorder related to the particular bacterial strain; i.e., the MIC of the compound, defined below, can be determined before use of the compounds in vivo with more complex living organisms is attempted. For cells outside the organism, multiple methods exist, and are well-known to those skilled in the art, to get the bacterial strain in contact with the compounds including, but not limited to, direct cell microinjection and numerous transmembrane carrier techniques.
It is a preferred embodiment of this invention that the Is bacteria which are inhibited by a compound of this invention are selected from the group consisting of genus Pseudomonas, Escherichia, Streptococcus, Staphylococcus, Mycobacteria, Enterococcus and Haemophilus.
A method for treating a bacterial infection in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound, salt or prodrug of a compound of this invention to the patient is a further presently preferred embodiment of this invention.
As used herein, the terms xe2x80x9ctreatxe2x80x9d, xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d refer to a method of alleviating or abrogating a bacteria-caused infection and/or its attendant symptoms.
A xe2x80x9cbacterial infectionxe2x80x9d refers to the multiplication of infection-causing bacteria in the body of a patient.
As used herein, xe2x80x9cadminister,xe2x80x9d xe2x80x9cadministeringxe2x80x9d or xe2x80x9cadministrationxe2x80x9d refers to the delivery of a compound, salt or prodrug of the present invention or of a pharmaceutical composition containing a compound, salt or prodrug of this invention to a patient in a manner suitable for the treatment of a bacterial infection.
A xe2x80x9cpatientxe2x80x9d refers to any higher organism that is susceptible to bacterial infections. Examples of such higher organisms include, without limitation, mice, rats, rabbits, dogs, cats, horses, cows, pigs, sheep, fish and reptiles. Preferably, xe2x80x9cpatientxe2x80x9d refers to a human being.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the bacterial infection being treated. Preferably, a therapeutically effective amount is an amount sufficient to cure the infection. By xe2x80x9ccuringxe2x80x9d is meant that the symptoms of active infection are eliminated including the elimination of excessive numbers of viable bacterial involved in the infection.
A method for preventing a bacterial infection in a patient comprising administering to said patient a prophylactically effective amount of a compound, salt or prodrug of a compound of this invention is a further presently preferred embodiment of this invention.
The term xe2x80x9cprophylactically effective amountxe2x80x9d means an amount of a compound or compounds of this invention sufficient to prevent the establishment of a clinically significant population of bacteria in a patient; that is, an amount capable of establishing an infection. Preferably, a prophylactically effective amount is that amount which prevents the establishment of any population of the target bacteria.
Another presently preferred embodiment of this invention that the bacterial infection which is treated with a compound, salt or prodrug of this invention consists of a bacterial infection caused by a bacteria selected from genus Pseudomonas, Escherichia, Staphylococcus, Streptococcus, Enterococcus, Mycobacteria and Haemophilus.
Likewise, it is a presently preferred embodiment of this invention that the bacterial infection which is treated with a compound, salt or prodrug of this invention is a bacterial infection caused by P. aeruginosa, E. coli, M. fortuitum, M. tuberculosis and H. influenzae. 
In another presently preferred embodiment of this invention, the bacterial infection being treated or prevented is selected from the group consisting of wound infection, burn lesion infection, urinary tract infection, enteritis, cystitis, peritonitis, gasterointestinal infection, colitis, pneumonia, strep throat, scarlet fever, impetigo, rheumatic fever, endocarditis, tuberculosis, bacterial meningitis, conjunctivitis, upper respiratory infection and endocarditis.
Finally, it is a presently preferred embodiment of this invention that the patient to be treated with a compound, salt or prodrug of this invention is a human.